1. Field of the Invention
The present invention relates to the use of S(+) ketoprofen to elicit an onset-hastened and enhanced analgesic response in mammalian organisms in need of such treatment, and to certain pharmaceutical compositions comprising unit dosage effective amounts of S(+) ketoprofen.
2. Description of the Art
Ketoprofen, also known as DL-2-(3-benzoylphenyl)-propionic acid, has the structural formula
The compound is well-known as a nonsteroidal anti-inflammatory drug having analgesic and antipyretic activity. In the United States, ketoprofen is marketed under the tradename Orudis.RTM.. Other tradenames or codenames include RP 19583, Alrheumat, Alrheumun, Capisten, Fastum, Iso-K, Kefenid, Ketopron, Lertus, Meprofen, Oruvail and Profenid. As Orudis.RTM., the drug is avadilable by prescription in the U.S. as capsules containing 25 mg, 50 mg dor 75 mg of ketoprofen, indicated for the acute or long-term treatment of the signs and symptoms of rheumatoid arthritis or osteoarthritis. Orudis.RTM. is recommended at a daily dose of 150 to 300 mg, divided in three or four doses. It is recommended that drug treatment begin at 75 mg three times or 50 mg four times a day. Small people may need smaller doses. Daily dosages should not exceed 300 mg per day. See also Physician's Desk Reference, 41st edition, 1987, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, NJ 07649, pp. 2179-2181. For mild to moderate pain and dysmenorrhea, a dose of 25 mg to 50 mg every 6 to 8 hours as needed was recently approved by the Food and Drug Administration ("F.D.A.").
As is apparent from its chemical nomenclature, ketoprofen is a racemic mixture. It is only the racemic mixture which has in fact ever been marketed. There have, however, been a few studies of the individual S(+) and R(-) isomers reported in the literature. These reflect that there is significant conversion of the R(-) isomer to the S(+) enantiomer, the latter being presumed by analogy with other 2-arylpropionic acids to be the active form of ketoprofen.
Hutt et al, J. Pharm. Pharmacol., 35, 693-704 (1983), reviewed the earlier work on the metabolic chiral inversion of 2-arylpropionic acids, including ibuprofen, which they indicate was the first substituted 2-arylpropionic acid conclusively shown to undergo the inversion as well as the most studied member of the group. The authors noted that early workers found no significant difference in in vivo activity among the R(-) and S(+) isomers and the racemic mixture of ibuprofen in three different animal models, but very large differences in vitro between the R(-) and S(+) isomers, ascribing this discrepancy to the virtually quantitative conversion of the R(-) to the active S(+) isomer in vivo. Hutt et al indicated similar properties for fenoprofen; the enantiomers of fenoprofen were reported to be of equal potency in animal test systems. No animal test information for the enantiomers of ketoprofen were reported. However, it was noted that ketoprofen, like fenoprofen, was known to undergo incorporation into triglycerides, an indirect indication of chiral inversion. Other indirect evidence was also discussed.
In the same paper, Hutt et al reported that, in contrast, for several other 2-arylpropionic acids, the inactive R(-) isomer was not converted in vivo to the active S(+) isomer as readily as ibuprofen and fenoprofen, although the conversion seemed to occur to some extent over time. Naproxen, they noted, has been the only compound marketed as the S(+) enantiomer to date. And in the case of indoprofen, the R(-) enantiomer was found to be about 20 times less pharmacologically active in rats and mice in vivo than the S(+) isomer. Hutt et al concluded:
It is likely that benefits will be obtained from the use of the S(+)-enantiomer of 2-arylpropionates as drugs as opposed to the racemates. This is only found at present in the case of naproxen. In cases of rapid inversion, the inactive R(-) isomer serves merely as a prodrug for the active S(+)-antipode. Where inversion is slow, the R(-) enantiomer is an unnecessary impurity in the active S(+) form. Use of the S(+)-enantiomer would permit reduction of the dose given, remove variability in rate and extent of inversion as a source of variability in therapeutic response and would reduce any toxicity arising from nonstereospecific mechanisms.
Thus, in cases of rapid inversion, such as ibuprofen and fenoprofen, where substantially equivalent in vivo responses have been reported for the individual enantiomers and the racemic drug, Hutt et al suggested that no benefits would be obtained from the use of the S(+) isomer because the inactive R(-) isomer merely acts as a prodrug for the active S(+) form. Contrariwise, in cases where chiral inversion is slow, e.g. naproxen and indoprofen, the use of the S(+) enantiomer is desirable for several reasons enumerated by Hutt et al. Indeed, naproxen has been reported to be marketed as the d-isomer for one of the reasons given by Hutt et al, i.e. to reduce side effects (Allison et al, "Naproxen," Chapter 9 in Anti-inflammatory and Anti-Rheumatic Drugs, eds. Rainsford and Path, CRC Press Inc., Boca Raton, Florida, 1985, p. 172).
Another general report on earlier work has been provided by Hutt et al in Clinical Pharmacokinetics, 9, 371-373 (1984). In this article on the importance of stereochemical considerations in the clinical pharmacokinetics of 2-arylpropionic acids, the authors tabulated relative potencies of the enantiomers of a number of 2-arylpropionic acidsin vivo and in vitro. The in vitro results showed the S or (+) isomer in each case to be the active species. In vivo, however, the results were not consistent across the entire class. Thus, the results for naproxen and indoprofen demonstrate the S or (+) isomer to be much more active in vivo, indicating a relatively slow inversion of the inactive R or (-) isomer to the active S or (+) isomer; the results for fenoprofen and ibuprofen, on the other hand, demonstrate the inactive R or (-) and the active S or (+) isomers tobe approximately equally effective in vivo, indicating a rapid inversion of R or (-) isomer to S or (+) isomer. The reference is silent, however, as to the activity of the enantiomers of ketoprofen.
Rendic et al, Il. Farmaco-Ed. Sci. 35(1), 51-59 (1980) investigated the binding properties of the + and - enantiomers of ketoprofen to human serum albumin (HSA). The authors indicated that their research was prompted by recent reports of the pharmacokinetic and therapeutic effects of racemic ketoprofen in humans, together with the generally accepted view that S-enantiomers of chiral derivatives of .alpha.-phenylpropionic acids have predominant, if not exclusive, anti-inflammatory activity. They found stereoselectivity in binding to HSA, especially at lower concentrations of ligands and of protein.
Lombard et al, IRCS Med. Sci. 13(10), 1025 (1985), found appreciable enrichment of S(+) ketoprofen in rat total liver homogenate after incubation with the racemic compound. Enrichment was already notable after 2 hours and no S(+) to R(-) conversion was found. The authors attributed the significant conversion of R(-) to S(+) in the liver to microsomal enzymes. In related research, Rossetti et al, IRCS Med. Sci. 14(3), 256-257 (1986), found that administration of racemic ketoprofen to rats gave significant enrichment of the S(+) isomer in urine.
The disposition of the enantiomers of racemic ketoprofen in normal rabbits as well as in rabbits with diminished renal function was studied by Abas et al, Clin. Exp. Pharmacol. Physiol, Suppl. 9, 41-42 (1985). Since acyl glucuronide formation accounts for most ketoprofen elimination in rabbits and man, the authors investigated whether intravenous administration of racemic ketoprofen leads to R to S inversion and whether the proportion of active S isomer in plasma would increase with renal dysfunction. Abas et al found that, in normal rats, 76% of R was inverted to S, assuming that unrecovered and recovered doses had the same enantiomeric composition. The authors stated: "The plasma AUC of the racemic compound was not increased in animals with i.v. uranyl induced renal failure (RF). This may be due to the high fraction of this enantiomer cleared by inversion rather than acyl glucuronide formation. (Congress abstract)." Thus, results in rabbits with impaired renal function were unclear.
Abas et al most recently reported on their studies of ketoprofen dispostion in normal and renally impaired rabbits in J. Pharmacol. Exp. Ther., 240(2), 637-641 (1987). The authors noted that ketoprofen is a racemate and like other 2-arylpropionic acid NSAID's, would be expected to undergo chiral inversion of the R to the S enantiomer, but that no data had been pulbished on the question. Indeed, their work reported in J. Pharmacol. Exp. Ther. appears to be the only instance in which the separate enantiomers of ketoprofen were separately administered in vivo.
In their work reported in J. Pharmacol. Exp. Ther., Abas et al showed enantiospecific inversion of R(-) to S(+) ketoprofen. However, the authors determined that only 9% of the R(-) enantiomer of ketoprofen was inverted to S, compared with 70% for its close structural analog, R(-) fenoprofen [Hayball et al, J. Pharmacol. Exp. Ther. 240(2), 631-636 (1987)]. Blood samples were collected before and at 0.08, 0.25, 0.5, 0.75 and 1.0 hour, then hourly until 8 hours after dosing. While Abas et al did not discuss any differences in amounts of inversion at the early time points, it might appear from their FIG. 2a that very substantial inversion of R to S occurred in the first hour after dosing, although the overall amount of conversion over time is not nearly as large.
Abas et al noted that their bound plus unbound ketoprofen concentration data had its limitations. The absence of plasma protein binding data for the individual enantiomers in rabbits meant it was impossible to calculate dispositional parameters for unbound drug; the authors were unable to examine selective clearance and distribution of the enantiomers independent of enantioselective effects on plasma protein binding. It would have been desirable to measure unbound ketoprofen; unfortunately, the assay methodology was not of sufficient sensitivity to allow such measurements.
Abas et al indicated that the implications of their findings were uncertain, given the complexities of competing clearance processes, and relevance to humans may depend on a variety of factors. See also Meffin et al, J. Pharmacol. Exp. Ther. 238, 280-287 (1986).
In summary, the current state of the art assumes that, in mammals, by analogy to another 2-arylpropionic acid NSAID's, the S(+) form is the active enantiomer of ketoprofen. The art recognizes that there is a significant conversion in vivo of R(-) to S(+), with no noted conversion of S(+) to R(-). However, there do not appear to be any animal experiments on efficacy of the separate enantiomers reported in the literature. The prior art, moreover, is conspicuously silent in respect to any onset-hastened/enhanced alleviation of mammalian pain utilizing whatever form of the ketoprofen drug species.